In utero estrogenic exposures and transgenerational risk for breast cancer

子宫内雌激素暴露和乳腺癌的跨代风险

• 批准号: 8043496
• 负责人: Sonia de Assis
• 金额: $ 7.44万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8043496
• 关键词: Accounting; Address; Adult; Affect; Animals; Biological Markers; Breast Cancer Prevention; Breast Cancer Risk Factor; Chronic Disease; DNA; DNA Methylation; Data; Daughter; Detection; Development; Developmental Biology; Diagnosis; Diet; Disease; Disease Outcome; Eating; Endocrine Disruptors; Environment; Environmental Risk Factor; Epigenetic Process; Estradiol; Estrogens; Exposure to; Family; Fatty acid glycerol esters; Female; Fetus; Fibrinogen; Figs - dietary; First Degree Relative; Future; Gene Expression; Gene Mutation; Generations; Genes; Genetic; Goals; Human; Knowledge; Lead; Life; Malignant - descriptor; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Methylation; Modeling; Modification; Monitor; Morphology; Mothers; Mutation; Partner in relationship; Pattern; Penetrance; Perinatal Exposure; Phenotype; Pilot Projects; Predisposition; Pregnancy; Pregnant Women; Prevention approach; Rattus; Recommendation; Recording of previous events; Research; Research Design; Risk; Risk Factors; Sprague-Dawley Rats; Staging; Woman; cancer prevention; cancer risk; dietary supplements; dimethylbenzanthracene; disorder risk; feeding; fetal programming; genome-wide; in utero; male; malignant breast neoplasm; mammary gland development; next generation; novel; offspring; pregnant; prevent; research study; trait; transmission process; tumor

DESCRIPTION (provided by applicant): In utero estrogenic exposures and transgenerational risk for breast cancer Background: Research in humans and animals suggests that what an expecting mother eats or is exposed to during pregnancy, can affect her offspring's susceptibility to disease in adulthood. Using a rat model, we have previously shown that a maternal diet high in fat during pregnancy is associated with increase in pregnancy estrogen levels and breast cancer risk in daughters. More recently, it was shown that what an expecting mother is exposed to during pregnancy affects risk of certain diseases not only in her offspring but subsequent generations as well. These effects are thought to be inheritable through epigenetic mechanisms. Objective/ hypothesis: We propose to study whether exposing pregnant rats to a high fat diet or an estrogen- supplemented diet will affect the risk of mammary cancer in the offspring and two subsequent generations. We hypothesize that in utero estrogenic exposures will increase the risk of mammary cancer of the female offspring (F1) and will be transmitted to the subsequent generations (F2/F3) through epigenetic mechanisms. A better understanding of how the in utero environment leads to modulation of breast cancer risk in the offspring and subsequent generations could have great implications for breast cancer prevention. Specific Aims: (1) Determine whether exposure of pregnant rats to estrogens or a high-fat diet is associated with increased mammary cancer risk in the offspring (F1) and subsequent generations(F2/F3). (2) Determine whether these in utero exposures are associated with changes in mammary gland developmental biology in the offspring (F1) and subsequent generations (F2/F3). (3) Determine whether the effects of these in utero exposures are transmitted to subsequent generations through epigenetic mechanisms. Study Design: Pregnant Sprague-Dawley rats will receive a high fat diet or an estradiol supplemented diet during gestation and mammary cancer development will be monitored in the offspring (F1). To address if the phenotype seen in the offspring is passed to subsequent generations, we will mate the female and male offspring (F1) and examine mammary cancer risk in the next generation (F2). Similarly, the F2 generation will be mated and mammary cancer examined in the offspring (F3). We will examine whether the mammary cancer phenotype in the F1, F2 and F3 generations is associated with changes in epigenetic and gene expression patterns in the mammary gland, employing genome-wide methylation and microarrays studies. We will also examine the mammary gland morphology to assess changes in mammary gland development.

描述（由申请人提供）： 在子宫雌激素暴露和乳腺癌背景的转世风险中：对人类和动物的研究表明，预期的母亲在怀孕期间会吃掉或暴露于怀孕期间，可能会影响其后代在成年后对疾病的敏感性。使用大鼠模型，我们以前已经表明，怀孕期间脂肪高的孕妇饮食与女儿的妊娠雌激素水平和乳腺癌风险的增加有关。最近，已经表明，在怀孕期间，期望的母亲不仅会影响某些疾病的风险，不仅在她的后代，而且会影响后代。这些影响被认为是通过表观遗传机制遗传的。客观/假设：我们建议研究将怀孕的大鼠暴露于高脂饮食或补充雌激素的饮食中是否会影响后代和随后两代的乳腺癌风险。我们假设在子宫内雌激素暴露将增加女性后代（F1）乳腺癌的风险，并将通过表观遗传机制传播到随后的世代（F2/F3）。更好地了解子宫内环境如何导致后代和后代的乳腺癌风险调节可能对预防乳腺癌的预防具有很大的影响。具体目的：（1）确定怀孕大鼠对雌激素或高脂饮食的暴露是否与后代（F1）和随后世代（F2/F3）的乳腺癌风险增加有关。 （2）确定子宫暴露在后代（F1）和后代（F2/F3）中的乳腺发育生物学的变化是否与乳腺发育生物学的变化有关。 （3）确定这些在子宫暴露中的影响是否通过表观遗传机制传播到后代。研究设计：怀孕的Sprague-Dawley大鼠将在妊娠期间接受高脂肪饮食或雌二醇补充饮食，并且将在后代（F1）中监测乳腺癌的发育。为了解决后代中看到的表型是否传递给后代，我们将与男性和男性后代（F1）交配，并检查下一代（F2）中的乳腺癌风险。同样，F2一代将在后代（F3）中进行配合并检查乳腺癌。我们将检查F1，F2和F3世代中的乳腺癌表型是否与采用全基因组甲基化和微阵列研究的乳腺表观遗传和基因表达模式的变化有关。我们还将检查乳腺形态，以评估乳腺发育的变化。